2. Academic Validation
  3. A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation

A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation

  • ACS Chem Neurosci. 2025 Jul 3. doi: 10.1021/acschemneuro.5c00111.
Yoshihisa Hirota 1,  Taiki Sato 2,  Rina Watanabe 1,  Kazuki Takeda 3 4,  Sho Sano 1,  Satoshi Asano 1,  Yuki Shibahashi 1,  Yumi Yasuda 2,  Yuta Takagi 1,  Yutaro Yamashita 1,  Wu YuXin 1,  Mikino Arakawa 1,  Yuri Maitani 1,  Vannessa Lawai 5,  Kurumi Nakagawa 1,  Natsuko Furukawa 2,  Atsuko Takeuchi 6,  Chisato Tode 6,  Maya Kamao 7,  Akimori Wada 8,  Zainab Ngaini 5,  Yoshitomo Suhara 2
Affiliations

Affiliations

  • 1 Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan.
  • 2 Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan.
  • 3 Laboratory of Toxicology, School of Veterinary Medicine, Kitasato University, E23-35-1, Towada, Aomori 034-0021, Japan.
  • 4 Department of Computer Science, Tokyo Institute of Technology, 4259-J3-1818, Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-0026, Japan.
  • 5 Faculty of Resource Science and Technology, Universiti Malaysia Sarawak, Kota Samarahan 94300 Sarawak, Malaysia.
  • 6 Instrumental Analysis Center, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
  • 7 Extension Center, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
  • 8 Department of Life Science for Organic Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
PMID: 40605819 DOI: 10.1021/acschemneuro.5c00111
Abstract

Vitamin K, primarily known for its roles in coagulation and bone metabolism, has recently been implicated in neuroprotection and neuronal differentiation, particularly via its bioactive form, menaquinone-4 (MK-4). Here, we synthesized 12 vitamin K compounds with retinoic acid-conjugated side chains and methyl ester modifications to enhance neuroactive properties. Among these, compound 7 demonstrated superior stability, robust transcriptional activation via steroid and xenobiotic receptor and retinoic acid receptor, and efficient induction of neuronal differentiation in mouse neural progenitor cells. Mechanistic analyzes revealed that Vitamin K activates metabotropic glutamate receptor 1 (mGluR1). Docking simulations confirmed its stronger mGluR1-binding affinity compared to MK-4. In vivo pharmacokinetics in C57BL/6 mice showed effective blood-brain barrier penetration, with compound 7 metabolizing into MK-4 over time. These findings establish compound 7 as a promising candidate for neurodegenerative disease therapies through its unique neuroactive mechanisms.

Keywords

biological metabolism; neuronal differentiation; nuclear receptor; pharmacokinetics; retinoic acid; vitamin K.

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